Recent exciting evidence has emerged on a critical mechanism of effector T cell (Teff) mediated by regulatory T (Treg) cells; the data show that Treg suppression can be blocked via IL-6 produced by dendritic cells (DC) (Medzhitov). Interestingly, both Treg function and IL-6 production appear aberrant in psoriasis, and their linkage may represent a novel mechanism of chronic autoimmune disease. Treg cells can be isolated from psoriatic skin, and our preliminary data suggests that regulatory cells found in psoriatic skin are deficient in their ability to inhibit Teff proliferation. This is also true for Treg cells isolated from peripheral blood of psoriatic patients. It is clear that Teff cells in psoriasis are numerous, highly proliferative, and pathogenic, because T cell specific interventions such as cyclosporin, FK506, anti-CD4, CTLA4-Ig, Alefacept and anti-CD3 confirm that T cell activation, specifically that of memory effector T ceils (Tmem/eff), is critical for sustaining a psoriatic lesion. In order to become pathogenic, Teff cells must have escaped Treg surveillance, which normally restrains pathogenic T cell proliferation. Although numerous laboratories have noted the presence of the cytokine IL-6 in psoriatic tissue, the specific functional role of IL-6 in psoriasis pathogenesis has not been clearly defined. Our preliminary data indicates that IL-6 secretion from isolated psoriatic epidermal cell preparations is quite high in the involved tissue and is only noted in extremely low amounts in uninvolved and normal tissue. This observation, coupled with our data demonstrating a deficiency in psoriatic Treg cells and the findings by Medzhitov, leads us to the hypothesis that: Regulatory T cells in psoriasis are blocked in their ability to suppress effector T cell responses due to the excessive levels of IL-6 present in involved areas of psoriatic tissue. Because Treg cells restrain T mem/eff cells, there is high value in investigating these ceils as a target for immunomodulatory intervention in human disease. Understanding Treg regulation, function and dysfunction in psoriasis is the focus of this proposal. Since Treg cells restrain both T memory (Tmem) and T mem/eff cells, there is high value in investigating these cells as a target for immunomodulatory intervention in human disease. Lesional psoriatic epidermis possesses an elevated allo-antigen presenting capacity and an abnormal ability to stimulate autologous T cells in the absence of exogenous antigen. The responsible antigen presenting cell (APC) appears activated and to express macrophage markers. Because activated macrophages are potent sources of IL-6 it is highly likely that these cells are providing signals for intralesional T cell activation and may themselves be stimulated to activation by IL-6 in the proper psoriatic microenvironment. However, the consequences of such autocrine stimulation in the context of a regulatory T cell environment has not been examined. Further, the local production of IL-6 may provide clues to the question of why psoriatic patients are capable of clearing routine immunological challenges without excessive Teff activation leading to generalized systemic or multiorgan autoimmunity. The local effect on Treg function which is delivered by 1L-6 may be exquisitely locally suppressing the Treg function specifically in lesional psoriasis skin.